The novel ZBTB5::JAK2 fusion gene reveals a new mechanism of kinase activation in Ph-like acute lymphoblastic leukemia

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a distinct subtype of B-ALL, exhibiting a kinase-activated gene expression profile similar to Philadelphia chromosome-positive (Ph+) ALL, yet lacking the BCR::ABL fusion. Despite the identification of numerous genetic aberrations and chromosomal rearrangements, particularly those involving the ABL-class or CRLF2/JAK pathways, as drivers and therapeutic targets, the genetic diversity and underlying pathogenic mechanisms of Ph-like ALL remain incompletely understood, posing challenges for diagnosis and treatment. Here, we identified a novel JAK2 fusion, ZBTB5::JAK2, in a Ph-like ALL patient, accompanied by a frequent KRAS12D mutation. Single-cell RNA sequencing (scRNA-seq) analysis suggests that the cell population with both high JAK2 and RAS signals may represent the leukemia stem cells in this patient. Overall design: To better understand molecular characteristics and pathogenic mechanisms of Ph-like ALL, we performed scRNA-seq on all leukocytes isolated from patients' PB at initial diagnosis and complete remission (after CART treatment).